CVT-313, A SPECIFIC AND POTENT INHIBITOR OF CDK2 THAT PREVENTS NEOINTIMAL PROLIFERATION

The activity of cyclin-dependent kinase 2 (CDK2) is essential for prog ression of cells from G(1) to the S phase of the mammalian cell cycle. CVT-313 is a potent CDK2 inhibitor, which was identified from a purin e analog library with an IC50 of 0.5 mu M in vitro. Inhibition was com petitive with respect to ATP (K-i = 95 nM), and selective CVT-313 had no effect on other, nonrelated ATP-dependent serine/threonine kinases, When added to CDK1 or CDK4, a 8.5- and 430-fold higher concentration of CVT-313 was required for half-maximal inhibition of the enzyme acti vity. In cells exposed to CVT-313, hyperphosphorylation of the retinob lastoma gene product was inhibited, and progression through the cell c ycle was arrested at the G(1)/S boundary, The growth of mouse, rat, an d human cells in culture was also inhibited by CVT-313 with the IC50 f or growth arrest ranging from 1.25 to 20 mu M. To evaluate the effects of CVT-313 in vivo, we tested this agent in a rat carotid artery mode l of restenosis, A brief intraluminal exposure of CVT-313 to a denuded rat carotid artery resulted in more than 80% inhibition of neointima formation. These observations suggest that CVT-313 is a promising cand idate for evaluation in other disease models related to aberrant cell proliferation.